Salmonella enterica is a Gram-negative pathogen of worldwide importance causing a variety of diseases including typhoid fever, enterocolitis and bacteremia. Following ingestion of contaminated products, bacteria access the human small intestine. Here, typhoidal species traverse the intestinal epithelium and are ingested by resident phagocytes. Replication and survival within innate immune cells enable Salmonella to cause systemic disease. To kill invading microbes, innate immune cells deploy reactive oxygen species, low pH and antimicrobial peptides (AMP). Amphipathic AMP interact with the bacterial cell surface inflicting membrane damage and death. Gram-negative pathogens have evolved to resist killing by AMP through modification of the lipopolysaccharide (LPS) component of their outer membrane. In Salmonella, LPS modification requires the highly conserved PhoP/Q two-component system. Within macrophage phagosomes, the membrane bound PhoQ sensor kinase is activated by low pH and AMP. PhoQ activation results in phosphorylation of PhoP, a cytosolic response regulator. Activated PhoP binds DNA and directs transcription of genes involved AMP resistance. Accordingly, the PhoP/Q system is absolutely required for intracellular growth and survival of Salmonella. In contrast, several genes activated by PhoP involved in LPS modification are dispensable during infection. Therefore, additional factors controlled by PhoP must be required in vivo. Preliminary data from our lab suggests that in addition to controlling LPS modification, the PhoP/Q system regulates phospholipid content of the Salmonella membrane. Using microarray and proteomic techniques, we have identified genes strongly upregulated upon PhoP activation and likely involved in lipid metabolism. We hypothesize that together;PhoP/Q-mediated alterations in outer membrane phospholipid content and LPS contribute to AMP resistance and innate immune evasion during infection. PUBLIC HEALTH RELEVANCE: Salmonellae are important Gram-negative bacterial pathogens of humans and animals causing a spectrum of enteric diseases, including gastroenteritis and enteric fever. PhoP and PhoQ comprise a bacterial two-component regulatory system, which is activated within macrophage phagosomes and required for virulence of Salmonellae for mice and humans, resistance to cationic antimicrobial peptides and acid pH, and survival within host cells. It is critical that we continue to advance knowledge of mechanisms that promote Salmonellae resistance to innate immune killing and alter recognition by innate immune receptors to develop new therapeutics and to understand mechanisms of immune avoidance common to many bacterial pathogens.